5-Nitroindazole-based compounds: further studies for activity optimization as anti-Trypanosoma cruzi agents

• Published in: Acta tropica 2022-10, Vol.234, p.106607-106607, Article 106607
• Main Authors: Fonseca-Berzal, Cristina, Ibáñez-Escribano, Alexandra, de Castro, Sonia, Escario, José A., Gómez-Barrio, Alicia, Arán, Vicente J.
• Format: Article
• Language: English
• Subjects: Chagas disease; In silico; In vitro; Indazole; Nitroheterocycle
• ISSN: 0001-706X; 1873-6254
• DOI: 10.1016/j.actatropica.2022.106607

•In silico approaches point to both good oral bioavailability and non-risks for 5-nitroindazoles.•Neither nitro nor halogen groups induce toxicity in 5-nitroindazole derivatives.•5-Nitroindazolinones show the highest selectivity on Trypanosoma cruzi.•Introduction of fluorine atoms has positive impacts on the trypanocidal profile. In this study, a new series of eleven 5-nitroindazole derivatives (10−20) and a related 6-nitroquinazoline (21) was synthesized and tested in vitro against different forms of the kinetoplastid parasite Trypanosoma cruzi, etiological agent of Chagas disease. Among these compounds, derivatives 11−14 and 17 showed trypanocidal profiles on epimastigotes (IC50 = 1.00−8.75 µM) considerably better than that of the reference drug benznidazole, BZ (IC50 = 25.22 µM). Furthermore, the lack of cytotoxicity observed for compounds 11, 12, 14, 17 and 18 over L929 fibroblasts, led to a notable selectivity (SI) on the extracellular replicative form of the parasite: SIEPI > 12.41 to > 256 µM. Since these five derivatives overpassed the cut-off value established by BZ (SIEPI ≥ 10), they were moved to a more specific assay against the intracellular and replicative form of T. cruzi, i.e, amastigotes. These molecules were not as active as BZ (IC50 = 0.57 µM) against this parasite form; however, all of them showed remarkable IC50 values lower than 7 µM. Special mention deserve compounds 12 and 17, whose SIAMA were > 246.15 and > 188.23, respectively. The results compiled in the present work, point to a positive impact over the trypanocidal activity of the electron withdrawing substituents introduced at position 2 of the N-2 benzyl moiety of these compounds, especially fluorine, i.e., derivatives 12 and 17. These outcomes, supported by the in silico prediction of good oral bioavailability and suitable risk profile, reinforce the 5-nitroindazole scaffold as an adequate template for preparing potential antichagasic agents. [Display omitted] Summary This work reports the activity of a synthetic series of eleven 5-nitroindazole derivatives and a related 6-nitroquinazoline, against different parasite forms of the etiological agent of Chagas disease, i.e., Trypanosoma cruzi.